Recent studies have shown that microdroplet reactions are markedly accelerated compared to the corresponding bulk-phase reactions. This raises the question whether all reactions can be sped up by this means. We present a counter example, and we show that the reaction mechanism in microdroplets can differ sharply from that in bulk, especially because of the distinct microdroplet surface environment. This analysis helps to guide us how to choose and control reactions in microdroplets and provides a possible perspective on utilizing microdroplet chemistry to scale up synthesis.

Many reactions show much faster kinetics in microdroplets than in the bulk phase. Most reported reactions in microdroplets mirror the products found in bulk reactions. However, the unique environment of microdroplets allows different chemistry to occur. In this work, we present the first chemoselective N‐alkylation of indoles in aqueous microdroplets via a three‐component Mannich‐type reaction without using any catalyst. In sharp contrast, bulk reactions using the same reagents with a catalyst yield exclusively C‐alkylation products. The N‐alkylation yield is moderate in microdroplets, up to 53 %. We extended the scope of the microdroplet reaction and obtained a series of new functionalized indole aminals, which are likely to have biological activities. This work clearly indicates that microdroplet reactions can show reactivity quite different from that of bulk‐phase reactions, which holds great potential for developing novel reactivities in microdroplets.

We report the first enantio- and diastereoselective 1,4-addition of butenolides to chromones. Both α,β- and β,γ-butenolide nucleophiles are compatible with the Zn-ProPhenol catalyst, and preactivation as the siloxyfurans is not required. The scope of electrophiles includes a variety of substituted chromones, as well as a thiochromone and a quinolone, and the resulting vinylogous addition products are generated in good yield (31 to 98%), diastereo- (3:1 to >30:1), and enantioselectivity (90:10 to 99:1 er). These Michael adducts allow rapid access to several natural product analogs, and can be easily transformed into a variety of other interesting scaffolds as well.

Introduction of unsaturation adjacent to the carbonyl drastically improves the reactivity of the Zn-ProPhenol catalyzed Mannich reactions between N-carbamoyl imines and a-branched ketones. Despite only a small change in the substrate acidity, the bimetallic catalyst can preferentially recognize and activate unsaturated ketones over their fully saturated counterparts, providing a chemo-, diastereo-, and enantioselective route to valuable β-aminoketones bearing both cyclic and acyclic quaternary stereocenters, which are common motifs in numerous biologically active alkaloids. Unsaturated ketones and imines with various substitution patterns are viable substrates, and the reaction can be performed on multi-millimole scale at low catalyst loading without impacting its efficiency. More importantly, the unsaturation introduced via the nucleophile provides a useful platform for structural diversification.